Alterations of amine neurotransmitter systems (norepinephrine (NE), serotonin (5HT) and dopamine (DA)) have been indirectly implicated in the pathophysiology of the major mental illnesses, depression and schizophrenia. We have applied new techniques to study cerebrospinal fluid (CSF), plasma and urine from drug-free patients with affective illness and schizophrenia using more sensitive and comprehensive characterization of the neurotransmitter systems as well as selective measures of post-synaptic function. New findings include the following: 1. The relationship between neurotransmitter systems, especially 5HT and DA, as measured by their major metabolites may be a marker of treatment response rather than absolute levels per se. There is also an important positive correlation between the NE metabolite and those of 5HT and DA. Data best fit a model whereby the strongest average influence is of the 5HT system on the DA one. Among a substantial group of seriously depressed patients, the only predictor of response was whether the 5HIAA/HVA correlation was high and similar to that observed in control subjects (good response) or was very weak (poor response). 2. Dysregulation of the noradrenergic system is the most consistently observed abnormality in depressed patients either as indexed by plasma NE response or shifts in the relative excretion of NE and its metabolites in urine. This, however, does not predict treatment response although it may distinguish unipolar from bipolar patients. 3. Direct measures of NE and its metabolites under resting vs stimulated conditions provide critical data that cannot be replaced or substituted for by such postsynaptic measures as beta receptors on lymphocytes or hydroxy melatonin output.